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Human Cell

pp 1–9 | Cite as

PAK1 silencing is synthetic lethal with CDK4/6 inhibition in gastric cancer cells via regulating PDK1 expression

  • Yan Qian
  • Xu Wu
  • Haixiao Wang
  • Guowei Hou
  • Xiao Han
  • Wei SongEmail author
Research Article

Abstract

Gastric cancer (GC) is one of the most common malignancies worldwide. The prognosis of GC is unsatisfied owning to widespread metastasis. P21-activated kinase 1 (PAK1), a member of serine/threonine kinases, is associated with the progression of multiple types of human cancers. Here, we demonstrated that CDK4/6 inhibitor reduced GC cell viability and decreased PAK1 expression. Consistently, PAK1 ablation increased GC cell sensitivity exposed to CDK4/6 inhibitor and promoted DNA damage. We also revealed PAK1 depletion notably affected PDK1-AKT pathway, and PDK1 overexpression totally abrogated the effect of PAK1 deletion on DNA damage in GC cells. Additionally, PDK1 overexpression also rescued the increased GC cell sensitivity towards CDK4/6 inhibitor and the cell cycle arrest caused by PAK1 depletion. Our findings, therefore, suggested that PAK1 silencing increased sensitivity to CDK4/6 inhibition in gastric cancer cells via PDK1–AKT pathway. We, therefore, thought PAK1 as a promising therapeutic target for the treatment of CDK4/6 inhibitor-resistant gastric cancer.

Keywords

P21-activated kinase 1 (PAK1) Gastric cancer (GC) PDK1 pathway Proliferation CDK4/6 inhibitor 

Notes

Author contributions

WS and YQ conceived and designed the experiments, XW and HXW analyzed and interpreted the results of the experiments, and GWH and XH performed the experiments.

Compliance with ethical standards

Conflict of interest

The authors state that there are no conflicts of interest to disclose.

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Copyright information

© Japan Human Cell Society and Springer Japan KK, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of GastricThe Affiliated Huaian No.1 People’s Hospital of Nanjing Medical UniversityHuai’anChina
  2. 2.Department of GastroenterlogyThe Affiliated Huaian No.1 People’s Hospital of Nanjing Medical UniversityHuai’anChina

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